We will be collaborating with centers which are generating genetic expression data on both human tumors and normal tissues to seek candidate proteins suitable for immune attack. These will be attacked by vaccinating mice bearing human molecules important to immune recognition of cancer (MHC; major histocompatibility complex molecules). Resulting responding T-cells will be cloned. If they are then confirmed to react with appropriate human tumors, the mouse T-cell receptors can be directly introduced into human T-cells where they have already been shown to function in vitro as well as in vivo (in clincal protocols against melanoma in the Surgery Branch). We have already identified thyroglobulin as a thyroid cancer antigen and cloned anti-thyroglobulin T-cells from vaccinated mice and a clinical procotol for differentiated thyroid cancer is now open to accrual. A new protocol targeting CD70, a protein on nearly all human renal cancer and many blood cancers is also in the final stages of development. We have also begun a clinical protocol to determine if resident lymphocytes in non-small cell lung cancer are reactive with tumor specific mutated neo-antigens and if so, whether they can be therapeutic if given patients using methods recently developed in the Surgery Branch (Tran et al, Science 2014).